Abstract: TH-OR079
CD11b Activation Ameliorates Lupus Nephritis by Reducing Myeloid Cell Infiltration, Including rs1143679 Carriers
Session Information
- Glomerular Diseases: Novel Mechanisms of Injury
October 22, 2026 | Location: Room 401, Convention Center
Abstract Time: 05:30 PM - 05:40 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Li, Xiaobo, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States
- Knott, Brenna, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States
- Reiser, Jochen, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States
- Niewold, Timothy B., Hospital for Special Surgery, New York, New York, United States
- Gupta, Vineet, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States
- Faridi, Hafeez, Chicago State University, Chicago, Illinois, United States
Background
Lupus nephritis (LN), a severe complication of systemic lupus erythematosus, is marked by immune complex deposition and immune cell infiltration in the kidney. Targeting B- and T-cells is highly effective in many, but not all, LN patients, suggesting that targeting innate immune cells may improve outcomes. CD11b is a key myeloid integrin that modulates cell adhesion and tissue recruitment. Notably, the rs1143679 variant in ITGAM (encoding CD11b) is a known lupus risk variant. Here, we hypothesized that targeting myeloid cell activation and kidney recruitment via CD11b could reduce inflammation and ameliorate LN, and that this strategy may be particularly relevant for rs1143679 carriers.
Methods
We analyzed human LN kidney scRNAseq data to identify CD11b+ cells and compared their signatures between rs1143679 carriers and non-carriers. Using a first-in-class CD11b-targeting small molecule (ONT01) in four murine models, including a humanized NSG model engrafted with rs1143679 patient PBMCs, we examined efficacy. A transgenic mouse expressing a gain-of-function mutation in CD11b was used to define molecular mechanism.
Results
CD11b+ myeloid cells were significantly enriched in LN kidneys and associated with disease severity. rs1143679 carriers exhibited markedly higher inflammatory signatures (NF-κB, interferon, myeloid recruitment) than non-carriers. CD11b activation with ONT01 reduced myeloid cell activation, kidney influx, glomerular injury, and proteinuria in LN models, with therapeutic benefits even after disease onset. In the humanized rs1143679 model, ONT01 lowered human CD11b+ cell infiltration and inflammatory cytokines (suPAR, CCL2, IL-6). Mechanistically, CD11b activation suppressed NF-κB and IRF3/7 signaling, reducing suPAR and CCL2 and affecting cell recruitment.
Conclusion
Our study establishes that increased influx of CD11b+ myeloid cells drives LN, with the rs1143679 mutation exacerbating this pathogenic signature. ONT01 reduces kidney recruitment of these cells and proteinuria, even in the rs1143679 mutation background. CD11b activation represents an innovative therapeutic mechanism for LN. A new clinical trial has recently been launched to evaluate this approach.
Funding
- NIDDK Support